Social Behavior and Gene Expression Disturbances in Mouse Models of Angelman Syndrome and Idic15 Autism

DSpace/Manakin Repository

Social Behavior and Gene Expression Disturbances in Mouse Models of Angelman Syndrome and Idic15 Autism

Citable link to this page

 

 
Title: Social Behavior and Gene Expression Disturbances in Mouse Models of Angelman Syndrome and Idic15 Autism
Author: Stoppel, David Christopher
Citation: Stoppel, David Christopher. 2014. Social Behavior and Gene Expression Disturbances in Mouse Models of Angelman Syndrome and Idic15 Autism. Doctoral dissertation, Harvard University.
Access Status: Full text of the requested work is not available in DASH at this time (“dark deposit”). For more information on dark deposits, see our FAQ.
Full Text & Related Files:
Abstract: Reciprocal changes in UBE3A gene dosage cause two neurodevelopmental disorders. Maternally inherited deletions of UBE3A cause Angelman syndrome, characterized by intellectual disability, motor defects, seizures, and a pathognomonic increased social motivation. Whereas maternally inherited triplications of UBE3A as in Idic15 Autism underlie decreased sociability and increased repetitive restrictive behaviors of this disorder. Identifying the cellular compartments and neuronal subtypes where excess and loss of Ube3a impair behavior is essential to understanding and potentially treating the disorders. In Chapter 2, we show that mouse models of maternal loss of UBE3A (Ube3a-mKO, Angelman syndrome) and triplication of UBE3A (Ube3a-2x, Idic15) have opposite effects on social behavioral and cortical gene expression. Social preference and social vocalizations are reduced in Ube3a-2x and increased in Ube3a-mKO mimicking the human phenotypes. Using a nuclear localizing signal tagged Ube3a transgenic mouse (Ube3a-NLS), we show that Ube3a acts in the nucleus to impair social behavior and cortical gene expression. Many of the genes reciprocally regulated by nuclear Ube3a are part of an Autism protein-interaction network. In Chapter 3, we demonstrate Ube3a-2x mice have increased aggression, an important Autism comorbidity. In contrast, maternal loss of Ube3a reduces aggression, consistent with the gregarious, amiable nature of individuals with Angelman syndrome. We then mapped the loci where increased Ube3a increases aggression. Increased aggression was observed when Ube3a was targeted to glutamatergic and vasopressinergic but not to GABAergic or oxytocinergic neurons. In Chapter 4, we show that in mice, social behavior is downregulated by social experience via Ube3a. In wild-type mice, altering their social environment strongly regulates their social behavior: individual housing causes hypersocial whereas group housing causes hyposocial behavior. In Ube3a-2x animals, group housing caused an excessive downregulation of social behavior whereas single housing fully rescued their social behavior deficits. By contrast, in Ube3a-mKO animals, the suppressive effects of group housing on social experience was largely blocked, suggesting Ube3a is required for this process. In summary, this thesis characterizes the role of UBE3A gene dosage in regulating social and aggression behaviors and identifies the subcellular compartment and neuronal subtypes where changes in Ube3a gene dosage disturb the homeostasis of these behaviors.
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:12274549
Downloads of this work:

Show full Dublin Core record

This item appears in the following Collection(s)

 
 

Search DASH


Advanced Search
 
 

Submitters